A novel multi-stage structural design optimization procedure has been developed for the weight minimization of hopper cars. The first stage in the design procedure involves topology optimization whereby optimal beam locations are determined within the hopper car wall structure design space. Through determination of optimal beam locations, a novel frame was designed which concentrates mass in critical regions of the hopper car. In the second stage, hexagonal honeycomb sandwich panels have been implemented in regions of low criticality and are optimized by means of a multiscale design optimization. By invoking the methodology in a case study, it is demonstrated that a mass savings as high as 16.36% can be yielded for a single hopper car without sacrificing rigidity, which can be translated into a reduction in greenhouse gas emissions of 13.09% based on available literature.